Hemes or porphinatoiron(II) complexes existing in hemoglobin and myoglobin play a role in the in vivo transport and storage of oxygen, and can reversibly bind and release molecular oxygen according to the partial pressure of oxygen. Since the 1970s, many reports have been made on studies to achieve oxygen adsorption-desorption functions similar to those of such natural hemes using synthetic porphinatoiron(II) complexes. Examples of early reports include J. P. Collman, Acc. Chem. Res., 10, 265 (1977) and F. Basolo, B. M. Hoffman, J. A. Ibers, ibid, 8, 384 (1975). Particularly, 5,10,15,20-tetrakis(α,α,α,α-o-pivalamidophenyl)porphinatoiron(II) complex (hereinafter referred to as “FeTpivPP complex”) (J. P. Collman, et al., J. Am. Chem. Soc., 97, 1427 (1975)) is known as a porphinatoiron(II) complex that can form a stable oxygen complex in ambient temperature conditions.
The FeTpivPP complex can reversibly bind and release molecular oxygen in ambient temperature in organic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran or N,N-dimethylformamide, in the presence of an axial base such as 1-alkylimidazole and 1-alkyl-2-methylimidazole. Further, the same oxygen adsorption-desorption functions is seen even under physiological conditions (water-phase system, pH 7.4, ≦40° C.) by incorporating this complex into a bilayer membrane vesicle consisting of phospholipids (e.g., E. Tsuchida et al., J. Chem. Soc., Dalton Trans., 1984, 1147 (1984)).
Here, the important point is that, firstly, as mentioned above, the addition of excess moles of the axial base molecule is required for the FeTpivPP complex to bind and release oxygen reversibly. However, certain imidazole derivatives that are widely used as axial base show pharmacological action, and often exhibit high internal toxicity. Also, when using phospholipid vesicles, the coexisting imidazole derivatives cause the morphology of the vesicles to become unstable. In order to reduce the amount of the axial base to a minimum, an imidazole derivative must be introduced into the molecule by covalent bonding.
The present inventors have considered that if, for example, an alkylimidazole derivative is covalently bonded as a substituent in the molecule of a porphinatoiron(II) complex, a stable oxygen carrier may be provided without external addition of an axial base, and have, so far, synthesized FeTpivPP analogues having substituents on the 2-position of the porphyrin ring, and observed reversible oxygen adsorption-desorption reaction for systems wherein such analogues were incorporated into phospholipid vesicles or human serum albumin (e.g., Japanese Patent Application Provisional Publication Nos. 59-164791, 59-162924 and 8-301873).
However, because the oxidation reaction of the central iron(II) is usually promoted in aqueous solutions than in organic solvents, the stability of the resulting oxygen complex is significantly low. In other words, reversible oxygen coordination activity is expressed only when the central iron of the porphyrin complex is in a divalent state; when the central iron is oxidized to form an iron(III) complex, the oxygen coordination activity is lost entirely (see, for example, Momentau et al., Chem. Rev., 110, 7690 (1994)). The aforementioned prior art technologies developed by the present inventors, wherein the porphinatoiron(II) complex is dispersed in water, not only have the effect of uniformly dissolving the porphinatoiron(II) complex in water, but also of extending the stability of the oxygen complex by providing a hydrophobic space in the vicinity of oxygen coordination site. However, when considering the use of such aqueous solution and dispersions of porphinatoiron(II) complex as artificial oxygen carriers, for example as a substitute for red blood cells, designing and synthesis of a porphyrin molecular structure that is capable of forming a more stable oxygen complex was desired.
The invention of the present application has been developed in view of the above situations, and an object of the present invention is to solve the above-mentioned problems of the prior art and to provide a porphyrin metal complex that is effective as an oxygen infusion.